The present invention relates to the field of oncology, particularly to polymorphous modifications of anticancer drugs and to complex compounds producing a synergistic antineoplastic effect. The subject of the invention is a new physically stable crystalline modification of ftorafur (INN, tegafur), namely, of 5-fluoro-1-(tetrahydro-2-furyl)uracil, which has an enhanced antineoplastic activity, compared with the modifications known heretofore, as well as new anticancer drugs based thereon, in the form of stable molecular complexes.
There is known a large number of medicinal substances and their combinations that are the result of comprehensive investigations of and improvements in antineoplastic substances. Chemotherapeutic substances effective with respect to malignant neoplasms are used in clinical practice. Though the results of such therapy have been improved substantially in recent years, it should be noted that in many cases the efficiency remains insignificant or insufficient for attaining the required degree of inhibiting the tumor growth and an essential extension of the life span of patients. Furthermore, most of the antineoplastic preparations are characterized by high toxicity, and this tells negatively on the process of treatment.
Ftorafur, 5-fluoro-1-(tetrahydro-2-furyl)uracil (INN, tegafur), synthesized by S. A. Giller with coworkers (U.S. Pat. No. 1,168,391) as a precursor of 5-fluorouracil (hereinafter referred to as 5FU) is an effective antineoplastic preparation and is widely used in treating various tumors, particularly, of the gastrointestinal tract and of the mammary gland.
Since tegafur is a sufficiently toxic compound, numerous attempts were made to reduce its toxicity and/or increase its effectiveness.
Pharmacopeial tegafur (corresponding to FS 42-1182-86) is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
The differential scanning calorimetry (DSC) curve of the pharmacopeial tegafur, shown in FIG. 7, displays two endothermal effects. The first, broad effect is in the range of 84.8-128.1xc2x0 C.; the second, melting effect is in the range of 172.3-192.0xc2x0 C. The UV spectrum is shown in FIG. 11.
In particular, over many years attempts have been made to modernize the very molecule of tegafur. For instance, in Belgian Patent No. 855121 there are described optically active isomers of 2xe2x80x2R- and 2xe2x80x2S-tegafur which is chemically a racemate. However, investigations carried out by different groups of scientists (for instance, by Yasumoto M. et al., xe2x80x9cJ. Med. Chem.xe2x80x9d, 1977, vol. 20, No. 12, 1592-1594 or by Horwitz J. P. et al., xe2x80x9cCancer Res.xe2x80x9d, 1975, vol. 35, 1301-1304) showed that the biological activity of both isomers is practically the same and does not differ from the activity of the racemate. The toxicity of one or another isomer does not display substantial differences from the initial substance either.
Furthermore, four crystalline forms of tegafur were produced and investigated (Uchida T. et al., xe2x80x9cChem. Pharm. Bull.xe2x80x9d, vol. 41, No. 9, 1632-1635). After treating the initial tegafur (corresponding to JP XII), xcex1-, xcex2-, xcex3-, and xcex4-modifications were isolated. These crystalline modifications differ in their x-ray powder diffraction patterns, IR spectra, and DSC curves. For producing an xcex1-form, tegafur was dissolved in warm acetone and allowed to crystallize at room temperature. Colorless columnar crystals were separated by filtration. Colorless prismatic crystals of the xcex2-form were prepared from a saturated methanol solution by evaporating the solvent with the help of a rotary evaporator. Crystals of the xcex3-form were obtained by heating the xcex2form at 130xc2x0 C. for 1 hour. Crystals of the xcex4-form were isolated by recrystallization from a methanol solution (very slow evaporation of methanol) at room temperature. None of the above-cited modifications offers essential therapeutic advantages.
From the above-stated a conclusion can be drawn that the problem of enhancing the tegafur activity by the synthesis or isomers or producing polymorphous modifications is still unsolved.
Concurrently, searches for compositionsxe2x80x94synergistic mixtures containing tegafur as the active substancexe2x80x94were carried out.
The discovery of a combination of medicinal substances, consisting of tegafur and uracil, was preceded by an idea that since 5-FU becomes metabolized too rapidly and loses activity in the organism, uracil may be used for inhibiting these processes (U.S. Pat. No. 5,534,513). It turned out that uracil as such does not display an antineoplastic activity, it has the property to potentiate the antineoplastic effect. An investigation of the effectiveness of a mixture of tegafur and uracil (tegafur:uracil molar ratio of 1:4) is discussed, e.g., in the work of Kagawa Y. et al., xe2x80x9cCancer Investigationxe2x80x9d, 1955, vol. 13, No. 5, 470-474.
Furthermore, there was produced and investigated a composition containing tegafur, uracil and folic acid (Sanchiz F. and Milla A., xe2x80x9cJpn. Journal Clin. Oncol.xe2x80x9d, 1994, vol. 24, No. 6, 322-326).
In such combination preparations an aspect of extreme importance is an optimal dosage of both the active component and of the substance potentiating the activity. It is desirable that the potentiating substance should be used in minimal doses (for reducing its own toxic effect) or that this substance per se should practically have no toxic effect. Presently known synergistic preparations containing tegafur, as the active component, and a potentiator are not always optimized with respect to both the qualitative and quantitative formulation of the components. For instance, uracil (which is usually used for potentiating the activity of tegafur) is a toxic compound, though its toxicity is less pronounced compared with other substances capable of potentiating the action of tegafur:thymine, thymine, thymidine or uridine (Fujita H., Experimental and Clinical Pharmacotherapy, Issue 12, Riga, 1983, p. 205).
Hence, the present-day therapy of neoplasms requires improved preparations used in oncology, as well as developing medicinal preparations displaying high antineoplastic activity along with minimized toxicity.
It is an object of the present invention to provide physically stable form of tegafur having an enhanced pharmacological activity. As a result of experiments it was unexpectedly found that an enhanced specific activity along with physical stability during a long period of time sufficient for commercial use is displayed by a hitherto-unknown metastable modification of tegafur, hereafter referred to as form V.
A novel form V comprises a light, xe2x80x9cairyxe2x80x9d white powder.
Form V is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
The carried out thermal analysis revealed in the novel form three pronounced peaks on the DSC curve.
The first peak is a transition of xcex1xe2x86x92xcex2 type in the region of 96.6-102xc2x0 C. The second and third peaks are a superposition of two endothermal effects: a xcex2xe2x86x92xcex3 transition in the range of 157.1-174.2xc2x0 C. and an effect of melting of the xcex3-form with the maximum temperature of 174xc2x0 C. superposed thereonto. The point of superposition of the second and third effects is in the neighborhood of 167.6xc2x0 C.
The UV spectrum of form V is shown in FIG. 10.
Form V of tegafur is prepared by dissolving a pharmacopeial tegafur substance or its individual polymorphous modifications in water, alcohol, or an alcoholic-aqueous mixture. The solvent should preferably be preheated to 40-65xc2x0 C. After that the resulting solution is introduced into a container with an anti-solvent (e.g., dimethyl ether, diethyl ether or chloroform) preliminarily cooled down to a temperature of at least 10xc2x0 C. The resulting precipitate is separated, the residues of the solvents are removed, and a crystalline powder of form V is obtained.
The novel crystalline modification of tegafur is physically stable and does not lose its properties on blending with pharmaceutically acceptable carriers or fillers, which makes this modification suitable for use in medicinal preparations. However, unexpectedly it was found that said form V has the property of forming completes with some organic molecules, including those having biological activity. In particular, complex compounds were obtained with 2,4-dioxo-6-methyl-1,2,3,-tetrahydropyrimidine (hereafter referred to as methyluracil) and with biologically active vegetable extracts produced, in particular from licorice (Radices Glycyrrhizae).
Complex compounds can be produced under definite technological conditions, leading to the formation of non-valence bonds between the molecules of tegafur and the molecules of organic compounds which enter into the interactions of such kind with tegafur.
There are three possible ways of synthesizing complex compounds. The first way envisages a single-step transfer of a physical mixture of tegafur and other organic molecules which are planned to be included in the composition of a complex into a high-energy (metastable) state. It was found that under these conditions tegafur passes into form V which is capable to form stable molecular complexes.
A physical mixture can be transferred into a high-energy state by different methods, the only condition in their carrying out being that they should yield form V of tegafur.
Such methods can be, for example, joint micronization (particularly, milling) or other known methods affecting the energy of a molecule.
The second way of producing complexes consists in blending a preliminarily prepared form V of tegafur with other components of the complex: an individual compound or a mixture of compounds which at the moment of blending are in a thermodynamically stable state.
The third way of producing complexes consists in blending a preliminarily prepared form V of tegafur with the second component of the complex, this second component already being in the high-energy state.
For producing complexes, it is possible to use, in particular: methyluracil (M. D. Mashkovskii, Drugs, 1997, Kharkov, vol. 2, p. 168 (in Russian)), xcex2-form of methyluracil (hereafter referred to as Betamecil) having a reduced toxicity (U.S. Pat. No. 5,543,147), different licorice extracts, e.g., Extractum Glycyrrhizae siccum (M. D. Mashkovskii, Drugs, 1997, Kharkov, vol. 1, pp. 345-346 (in Russian)).
The molecular complex tegafur-methyluracil in the molar ratio of 1:2 (complex compound 1a) is a white fine-crystalline powder, and it is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
The DSC curve of compound 1a is shown in FIG. 8. The curve displays two endothermal effects. The first effect of xcex1xe2x86x92xcex2 type is in the range of 117.1-132xc2x0 C. The second effect of melting of xcex2-form is in the range of 149.9-167.1xc2x0 C.
The UV spectrum of compound 1a, characterizing the individuality of this substance, is shown in FIG. 12.
The molecular complex tegafur-methyluracil in the molar ratio of 1:1 (complex compound 1b) is a white fine-crystalline powder, and it is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
The complex tegafur-licorice (complex compound 2) is amorphous in terms of x-ray diffraction pattern analysis and comprises a light clumping yellow powder with a brownish hue.
The DSC curve of compound 2, shown in FIG. 9, displays e combination of two endothermal effects: a broad effect lies in the range of 98.2-125.0xc2x0 C.; the second effect, accompanied by decomposition of the substance, lies in the range of 125.0-171.5xc2x0 C.
The UV spectrum of compound 2, which supports the individuality of this substance, is shown in FIG. 13.
Form V excels in solubility the hitherto-known modifications of tegafur. Moreover, the novel form of tegafur, compared with the hitherto-known polymorphous modifications thereof, has an enhanced specific activity. Complex compounds display a still greater specific activity (compared not only with pharmacopeial tegafur, but also with novel form V), i.e., there takes place potentiation of the pharmacological effect.
The obtained novel crystalline modification of ftorafur and complex compounds based on this modification may find extensive application in medicine for treating oncological diseases. This will make it possible to broaden the range of medicaments acting on tumor cells and, correspondingly, to increase the effectiveness of treating patients suffering from malignant neoplasms.